Zhang Jia, Wang Tao, Bi Jianbin, Ke Mengyun, Ren Yifan, Wang Mengzhou, Du Zhaoqing, Liu Wuming, Hu Liangshuo, Zhang Xiaogang, Liu Xuemin, Wang Bo, Wu Zheng, Lv Yi, Meng Lingzhong, Wu Rongqian
National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, 124, 76 West Yanta Road, Xi'an, Shaanxi, 710061, China.
Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Cell Biosci. 2023 Mar 24;13(1):64. doi: 10.1186/s13578-023-01010-w.
Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress.
HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury.
HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes.
HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.
内质网（ER）应激在各种肝脏疾病的发生和发展中起重要作用。然而，目前尚无有效的预防和治疗策略。我们旨在确定热休克因子2结合蛋白（HSF2BP）在内质网应激中的作用。
在衣霉素诱导的内质网应激过程中，检测小鼠和培养的肝细胞中HSF2BP的表达，并在肝细胞特异性HSF2BP转基因（TG）和敲除（KO）小鼠中评估其在内质网应激中的重要性。在肝缺血再灌注（I/R）损伤中进一步探讨HSF2BP对内质网应激的影响及其机制。
在衣霉素诱导的小鼠和培养的肝细胞内质网应激过程中，HSF2BP表达显著上调。衣霉素处理后，HSF2BP过表达小鼠的肝损伤和内质网应激减轻，但与对照组相比，HSF2BP敲除小鼠的肝损伤和内质网应激加重。在肝I/R损伤中，HSF2BP表达显著上调，HSF2BP过表达小鼠的肝损伤和炎症减轻。这些改善与内质网应激的抑制有关。然而，在肝细胞特异性HSF2BP敲除小鼠中，这些结果相反。HSF2BP过表达增加了细胞质CDC73水平并抑制了JNK信号通路。使用siRNA敲低CDC73消除了HSF2BP过表达对缺氧/复氧（H/R）诱导的肝细胞内质网应激的保护作用。
HSF2BP是内质网应激中一个以前未被鉴定的调节因子，可能通过调节CDC73亚细胞定位发挥作用。HSF2BP靶向治疗内质网应激相关肝病的可行性值得未来研究。
